The goal of our proposed study is to elucidate the toxicological effects of exposure to estrogenic xenobiotics on the cardiac system, and to define the underlying pharmacological mechanisms of actions of these agents. We will also investigate the molecular basis for the sex-specific susceptibility to estrogenic xenobiotics-induced cardio-toxic effect. Estrogenic endocrine-disrupting chemicals (EDCs) are structurally diverse compounds that mimic, or antagonize the actions of endogenous estrogens. A particularly significant example of EDCs to human health is the nearly ubiquitous estrogenic xenobiotic bisphenol A (BPA). Estrogenic EDCs have the ability to impact the actions of endogenous estrogen, i.e. 17?-estradiol (E2), and it is increasingly recognized that BPA and other EDCs can have harmful effects on the reproductive, nervous and immune systems. A notable gap in our current knowledge on health risks of EDC exposure is its impact on cardiac physiology and health. Importantly, a recent epidemiologic study has shown that in the US adult population, higher urine BPA concentrations are associated with adverse health effects, including cardiovascular disease (Lang et al, 2008). This new evidence highlights the critical need to understand the effects of exposure to environmentally relevant concentrations of estrogenic EDCs on the heart, which are currently unknown. This fundamental lack of knowledge regarding the effects of estrogenic xenobiotics in the heart hinders effective protection against environmental cardiac risk factors, and the development of preventive-therapeutic strategies. We present compelling preliminary results showing that exposure to environmentally or physiologically relevant low-dose of BPA and E2 rapidly promotes arrhythmogenic activity in female ventricular myocytes and female hearts, but not in male. We have shown that the underlying mechanism of the rapid pro-arrhythmic effects of estrogenic agents likely involve increased spontaneous Ca leak from the sarcoplasmic reticulum, and that the mechanism of the sex-specific susceptibility to EDCs involves the opposing effects of membrane estrogen receptors (ER)s. These findings lead to our central hypothesis that E2 and estrogenic EDCs, via activation of membrane associated ER mechanisms, alter cardiac Ca2+ handling in a sex-specific manner, and that the actions of at least some estrogenic agents contribute to arrhythmogenesis in female hearts. We propose three Specific Aims to address this hypothesis: Aim 1 is to determine the cellular mechanism(s) underlying the pro- arrythmogenic effects of EDCs and E2 in rat ventricular myocytes; Aim 2 is to define the molecular basis for the sex-specificity of susceptibility to rapid E2/EDC effects on contractile function and arrhythmogenesis of ventricular myocytes; and Aim 3 is to determine the effects of E2/EDCs on cardiac arrhythmias at the whole organ level, especially during pathologic stress, including catecholamine stimulation and ischemia, and explore potential preventive/therapeutic strategies for protection against such arrhythmias. PUBLIC HEALTH RELEVANCE: Our proposed study investigates the toxicological effects and underlying mechanism of exposure to estrogenic xenobiotics and other environmental estrogenic compounds on the cardiac system, particularly in women. These studies have high clinical relevance, particularly with respect to arrhythmias in women in the at risk population. The results will provide critical knowledge for the development of protective measures against environmental estrogenic cardiac risk factors, and the development of novel preventive or therapeutic strategies for cardiac diseases related to these risk factors.